Molecules

Editorial

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3 pages, 127 KiB

Open AccessEditorial

Advances in Heparins and Related Research. An Epilogue

by Jawed Fareed, Peter Bacher and Walter Jeske

Molecules 2018, 23(2), 390; https://doi.org/10.3390/molecules23020390 - 12 Feb 2018

Cited by 5 | Viewed by 3016

Abstract

The discovery of heparin in 1916 by Jay McLean, a medical student at Johns Hopkins University, not only provided a universal anticoagulant, but also laid the foundation for the discipline of hemostasis and thrombosis[...] Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

4 pages, 154 KiB

Open AccessEditorial

Looking Forward to the Future of Heparin: New Sources, Developments and Applications

by Giangiacomo Torri and Giuseppe Cassinelli

Molecules 2018, 23(2), 293; https://doi.org/10.3390/molecules23020293 - 31 Jan 2018

Cited by 6 | Viewed by 3510

Abstract

The seven reviews and the eleven articles in this special issue provide an updated survey of recent research and developments in the ever-growing field of heparin, along with low molecular weight heparins (LMWHs) and glycosaminoglycans (GAGs). Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

2 pages, 139 KiB

Open AccessEditorial

Remembering Professor Benito Casu (1927–2016)

by Giangiacomo Torri and Giuseppe Cassinelli

Molecules 2018, 23(2), 292; https://doi.org/10.3390/molecules23020292 - 31 Jan 2018

Cited by 1 | Viewed by 2586

Abstract

Heparin and related drugs have contributed in so many different ways to the drug discovery process, and have provided a platform to understand the pathophysiology of vascular and inflammatory diseases for nearly 100 years. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

Research

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3161 KiB

Open AccessArticle

Extended Physicochemical Characterization of the Synthetic Anticoagulant Pentasaccharide Fondaparinux Sodium by Quantitative NMR and Single Crystal X-ray Analysis

by William de Wildt, Huub Kooijman, Carel Funke, Bülent Üstün, Afranina Leika, Maarten Lunenburg, Frans Kaspersen and Edwin Kellenbach

Molecules 2017, 22(8), 1362; https://doi.org/10.3390/molecules22081362 - 17 Aug 2017

Cited by 8 | Viewed by 6083

Abstract

Fondaparinux sodium is a synthetic pentasaccharide representing the high affinity antithrombin III binding site in heparin. It is the active pharmaceutical ingredient of the anticoagulant drug Arixtra^®. The single crystal X-ray structure of Fondaparinux sodium is reported, unequivocally confirming both structure [...] Read more.

Fondaparinux sodium is a synthetic pentasaccharide representing the high affinity antithrombin III binding site in heparin. It is the active pharmaceutical ingredient of the anticoagulant drug Arixtra^®. The single crystal X-ray structure of Fondaparinux sodium is reported, unequivocally confirming both structure and absolute configuration. The iduronic acid adopts a somewhat distorted chair conformation. Due to the presence of many sulfur atoms in the highly sulfated pentasaccharide, anomalous dispersion could be applied to determine the absolute configuration. A comparison with the conformation of Fondaparinux in solution, as well as complexed with proteins is presented. The content of the solution reference standard was determined by quantitative NMR using an internal standard both in 1999 and in 2016. A comparison of the results allows the conclusion that this method shows remarkable precision over time, instrumentation and analysts. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

Molecular Weights of Bovine and Porcine Heparin Samples: Comparison of Chromatographic Methods and Results of a Collaborative Survey

by Sabrina Bertini, Giulia Risi, Marco Guerrini, Kevin Carrick, Anita Y. Szajek and Barbara Mulloy

Molecules 2017, 22(7), 1214; https://doi.org/10.3390/molecules22071214 - 19 Jul 2017

Cited by 11 | Viewed by 5911

Abstract

In a collaborative study involving six laboratories in the USA, Europe, and India the molecular weight distributions of a panel of heparin sodium samples were determined, in order to compare heparin sodium of bovine intestinal origin with that of bovine lung and porcine [...] Read more.

In a collaborative study involving six laboratories in the USA, Europe, and India the molecular weight distributions of a panel of heparin sodium samples were determined, in order to compare heparin sodium of bovine intestinal origin with that of bovine lung and porcine intestinal origin. Porcine samples met the current criteria as laid out in the USP Heparin Sodium monograph. Bovine lung heparin samples had consistently lower average molecular weights. Bovine intestinal heparin was variable in molecular weight; some samples fell below the USP limits, some fell within these limits and others fell above the upper limits. These data will inform the establishment of pharmacopeial acceptance criteria for heparin sodium derived from bovine intestinal mucosa. The method for MW determination as described in the USP monograph uses a single, broad standard calibrant to characterize the chromatographic profile of heparin sodium on high-resolution silica-based GPC columns. These columns may be short-lived in some laboratories. Using the panel of samples described above, methods based on the use of robust polymer-based columns have been developed. In addition to the use of the USP’s broad standard calibrant for heparin sodium with these columns, a set of conditions have been devised that allow light-scattering detected molecular weight characterization of heparin sodium, giving results that agree well with the monograph method. These findings may facilitate the validation of variant chromatographic methods with some practical advantages over the USP monograph method. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

Combining NMR Spectroscopy and Chemometrics to Monitor Structural Features of Crude Hep-arin

by Lucio Mauri, Maria Marinozzi, Giulia Mazzini, Richard E. Kolinski, Michael Karfunkle, David A. Keire and Marco Guerrini

Molecules 2017, 22(7), 1146; https://doi.org/10.3390/molecules22071146 - 8 Jul 2017

Cited by 23 | Viewed by 8334

Abstract

Because of the complexity and global nature of the heparin supply chain, the control of heparin quality during manufacturing steps is essential to ensure the safety of the final active pharmaceutical ingredient (API). For this reason, there is a need to develop consistent [...] Read more.

Because of the complexity and global nature of the heparin supply chain, the control of heparin quality during manufacturing steps is essential to ensure the safety of the final active pharmaceutical ingredient (API). For this reason, there is a need to develop consistent analytical methods able to assess the quality of heparin early in production (i.e., as the crude heparin before it is purified to API under cGMP conditions). Although a number of analytical techniques have been applied to characterize heparin APIs, few of them have been applied for crude heparin structure and composition analyses. Here, to address this issue, NMR spectroscopy and chemometrics were applied to characterize 88 crude heparin samples. The samples were also analyzed by strong anion exchange HPLC (SAX-HPLC) as an orthogonal check of the purity levels of the crudes analyzed by NMR. The HPLC data showed that the chemometric analysis of the NMR data differentiated the samples based on their purity. These orthogonal approaches differentiated samples according their glycosaminoglycan (GAG) composition and their mono and disaccharide composition and structure for each GAG family (e.g., heparin/heparan, dermatan sulfate, and chondroitin sulfate A). Moreover, quantitative HSQC and multivariate analysis (PCA) were used to distinguish between crude heparin of different animal and tissue sources. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

Characterization of Danaparoid Complex Extractive Drug by an Orthogonal Analytical Approach

by Cristina Gardini, Elena Urso, Marco Guerrini, René Van Herpen, Pauline De Wit and Annamaria Naggi

Molecules 2017, 22(7), 1116; https://doi.org/10.3390/molecules22071116 - 5 Jul 2017

Cited by 12 | Viewed by 6469

Abstract

Danaparoid sodium salt, is the active component of ORGARAN, an anticoagulant and antithrombotic drug constituted of three glycosaminoglycans (GAGs) obtained from porcine intestinal mucosa extracts. Heparan sulfate is the major component, dermatan sulfate and chondroitin sulfate being the minor ones. Currently dermatan sulfate [...] Read more.

Danaparoid sodium salt, is the active component of ORGARAN, an anticoagulant and antithrombotic drug constituted of three glycosaminoglycans (GAGs) obtained from porcine intestinal mucosa extracts. Heparan sulfate is the major component, dermatan sulfate and chondroitin sulfate being the minor ones. Currently dermatan sulfate and chondroitin sulfate are quantified by UV detection of their unsaturated disaccharides obtained by enzymatic depolymerization. Due to the complexity of danaparoid biopolymers and the presence of shared components, an orthogonal approach has been applied using more advanced tools and methods. To integrate the analytical profile, 2D heteronuclear single quantum coherence (HSQC) NMR spectroscopy was applied and found effective to identify and quantify GAG component signals as well as those of some process signatures of danaparoid active pharmaceutical ingredient (API) batches. Analyses of components of both API samples and size separated fractions proceeded through the determination and distribution of the molecular weight (Mw) by high performance size exclusion chromatographic triple detector array (HP-SEC-TDA), chain mapping by LC/MS, and mono- (¹H and ¹³C) and bi-dimensional (HSQC) NMR spectroscopy. Finally, large scale chromatographic isolation and depolymerization of each GAG followed by LC/MS and 2D-NMR analysis, allowed the sequences to be defined and components to be evaluated of each GAG including oxidized residues of hexosamines and uronic acids at the reducing ends. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies

by Antonella Bisio, Elena Urso, Marco Guerrini, Pauline De Wit, Giangiacomo Torri and Annamaria Naggi

Molecules 2017, 22(7), 1051; https://doi.org/10.3390/molecules22071051 - 24 Jun 2017

Cited by 16 | Viewed by 7071

Abstract

A number of low molecular weight heparin (LMWH) products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic [...] Read more.

A number of low molecular weight heparin (LMWH) products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic and pharmacodynamics differences. While enoxaparin has been extensively investigated, little information is available regarding the LMWH dalteparin. The present study is focused on the detailed structural characterization of Fragmin^® by LC-MS and NMR applied both to the whole drug and to its enzymatic products. For a more in-depth approach, size homogeneous octasaccharide and decasaccharide components together with their fractions endowed with high or no affinity toward antithrombin were also isolated and their structural profiles characterized. The combination of different analytical strategies here described represents a useful tool for the assessment of batch-to-batch structural variability and for comparative evaluation of structural features of biosimilar products. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessFeature PaperArticle

Albumin and Hyaluronic Acid-Coated Superparamagnetic Iron Oxide Nanoparticles Loaded with Paclitaxel for Biomedical Applications

by Elena Vismara, Chiara Bongio, Alessia Coletti, Ravit Edelman, Andrea Serafini, Michele Mauri, Roberto Simonutti, Sabrina Bertini, Elena Urso, Yehuda G. Assaraf and Yoav D. Livney

Molecules 2017, 22(7), 1030; https://doi.org/10.3390/molecules22071030 - 22 Jun 2017

Cited by 57 | Viewed by 11015

Abstract

Super paramagnetic iron oxide nanoparticles (SPION) were augmented by both hyaluronic acid (HA) and bovine serum albumin (BSA), each covalently conjugated to dopamine (DA) enabling their anchoring to the SPION. HA and BSA were found to simultaneously serve as stabilizing polymers of Fe [...] Read more.

Super paramagnetic iron oxide nanoparticles (SPION) were augmented by both hyaluronic acid (HA) and bovine serum albumin (BSA), each covalently conjugated to dopamine (DA) enabling their anchoring to the SPION. HA and BSA were found to simultaneously serve as stabilizing polymers of Fe₃O₄·DA-BSA/HA in water. Fe₃O₄·DA-BSA/HA efficiently entrapped and released the hydrophobic cytotoxic drug paclitaxel (PTX). The relative amount of HA and BSA modulates not only the total solubility but also the paramagnetic relaxation properties of the preparation. The entrapping of PTX did not influence the paramagnetic relaxation properties of Fe₃O₄·DA-BSA. Thus, by tuning the surface structure and loading, we can tune the theranostic properties of the system. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessFeature PaperArticle

Self-Assembled Lipid Nanoparticles for Oral Delivery of Heparin-Coated Iron Oxide Nanoparticles for Theranostic Purposes

by Eleonora Truzzi, Chiara Bongio, Francesca Sacchetti, Eleonora Maretti, Monica Montanari, Valentina Iannuccelli, Elena Vismara and Eliana Leo

Molecules 2017, 22(6), 963; https://doi.org/10.3390/molecules22060963 - 9 Jun 2017

Cited by 29 | Viewed by 5681

Abstract

Recently, solid lipid nanoparticles (SLNs) have attracted increasing attention owing to their potential as an oral delivery system, promoting intestinal absorption in the lymphatic circulation which plays a role in disseminating metastatic cancer cells and infectious agents throughout the body. SLN features can [...] Read more.

Recently, solid lipid nanoparticles (SLNs) have attracted increasing attention owing to their potential as an oral delivery system, promoting intestinal absorption in the lymphatic circulation which plays a role in disseminating metastatic cancer cells and infectious agents throughout the body. SLN features can be exploited for the oral delivery of theranostics. Therefore, the aim of this work was to design and characterise self-assembled lipid nanoparticles (SALNs) to encapsulate and stabilise iron oxide nanoparticles non-covalently coated with heparin (Fe@hepa) as a model of a theranostic tool. SALNs were characterised for physico-chemical properties (particle size, surface charge, encapsulation efficiency, in vitro stability, and heparin leakage), as well as in vitro cytotoxicity by methyl thiazole tetrazolium (MTT) assay and cell internalisation in CaCo-2, a cell line model used as an indirect indication of intestinal lymphatic absorption. SALNs of about 180 nm, which are stable in suspension and have a high encapsulation efficiency (>90%) were obtained. SALNs were able to stabilise the heparin coating of Fe@hepa, which are typically unstable in physiological environments. Moreover, SALNs–Fe@hepa showed no cytotoxicity, although their ability to be internalised into CaCo-2 cells was highlighted by confocal microscopy analysis. Therefore, the results indicated that SALNs can be considered as a promising tool to orally deliver theranostic Fe@hepa into the lymphatic circulation, although further in vivo studies are needed to comprehend further potential applications. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

Structure-Activity Relationships of Bioengineered Heparin/Heparan Sulfates Produced in Different Bioreactors

by Ha Na Kim, John M. Whitelock and Megan S. Lord

Molecules 2017, 22(5), 806; https://doi.org/10.3390/molecules22050806 - 15 May 2017

Cited by 12 | Viewed by 6391

Abstract

Heparin and heparan sulfate are structurally-related carbohydrates with therapeutic applications in anticoagulation, drug delivery, and regenerative medicine. This study explored the effect of different bioreactor conditions on the production of heparin/heparan sulfate chains via the recombinant expression of serglycin in mammalian cells. Tissue [...] Read more.

Heparin and heparan sulfate are structurally-related carbohydrates with therapeutic applications in anticoagulation, drug delivery, and regenerative medicine. This study explored the effect of different bioreactor conditions on the production of heparin/heparan sulfate chains via the recombinant expression of serglycin in mammalian cells. Tissue culture flasks and continuously-stirred tank reactors promoted the production of serglycin decorated with heparin/heparan sulfate, as well as chondroitin sulfate, while the serglycin secreted by cells in the tissue culture flasks produced more highly-sulfated heparin/heparan sulfate chains. The serglycin produced in tissue culture flasks was effective in binding and signaling fibroblast growth factor 2, indicating the utility of this molecule in drug delivery and regenerative medicine applications in addition to its well-known anticoagulant activity. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

A Fluorescent Probe for Glycosaminoglycans Applied to the Detection of Dermatan Sulfate by a Mix-and-Read Assay

by Melissa Rappold, Ulrich Warttinger and Roland Krämer

Molecules 2017, 22(5), 768; https://doi.org/10.3390/molecules22050768 - 9 May 2017

Cited by 14 | Viewed by 7941

Abstract

Glycosaminoglycans are complex biomolecules of great biological and medical importance. The quantification of glycosaminoglycans, in particular in complex matrices, is challenging due to their inherent structural heterogeneity. Heparin Red, a polycationic, fluorescent perylene diimide derivative, has recently emerged as a commercial probe for [...] Read more.

Glycosaminoglycans are complex biomolecules of great biological and medical importance. The quantification of glycosaminoglycans, in particular in complex matrices, is challenging due to their inherent structural heterogeneity. Heparin Red, a polycationic, fluorescent perylene diimide derivative, has recently emerged as a commercial probe for the convenient detection of heparins by a mix-and-read fluorescence assay. The probe also detects glycosaminoglycans with a lower negative charge density than heparin, although with lower sensitivity. We describe here the synthesis and characterization of a structurally related molecular probe with a higher positive charge of +10 (vs. +8 of Heparin Red). The superior performance of this probe is exemplified by the quantification of low dermatan sulfate concentrations in an aqueous matrix (quantification limit 1 ng/mL) and the detection of dermatan sulfate in blood plasma in a clinically relevant concentration range. The potential applications of this probe include monitoring the blood levels of dermatan sulfate after administration as an antithrombotic drug in the absence of heparin and other glycosaminoglycans. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

The Impact of the Low Molecular Weight Heparin Tinzaparin on the Sensitization of Cisplatin-Resistant Ovarian Cancers—Preclinical In Vivo Evaluation in Xenograft Tumor Models

by Thomas Mueller, Daniel Bastian Pfankuchen, Kathleen Wantoch von Rekowski, Martin Schlesinger, Franziska Reipsch and Gerd Bendas

Molecules 2017, 22(5), 728; https://doi.org/10.3390/molecules22050728 - 3 May 2017

Cited by 14 | Viewed by 5628

Abstract

Resistance formation of tumors against chemotherapeutics is the major obstacle in clinical cancer therapy. Although low molecular weight heparin (LMWH) is an important component in oncology referring to guideline-based antithrombotic prophylaxis of tumor patients, a potential interference of LMWH with chemoresistance is unknown. [...] Read more.

Resistance formation of tumors against chemotherapeutics is the major obstacle in clinical cancer therapy. Although low molecular weight heparin (LMWH) is an important component in oncology referring to guideline-based antithrombotic prophylaxis of tumor patients, a potential interference of LMWH with chemoresistance is unknown. We have recently shown that LMWH reverses the cisplatin resistance of A2780cis human ovarian cancer cells in vitro. Here we address the question whether this LMWH effect is also valid under in vivo conditions. Therefore, we established tumor xenografts of A2780 and cisplatin resistant A2780cis cells in nude mice and investigated the impact of daily tinzaparin applications (10 mg/kg BW) on anti-tumor activity of cisplatin (6 mg/kg BW, weekly) considering the tumor growth kinetics. Intratumoral platinum accumulation was detected by GF-AAS. Xenografts of A2780 and A2780cis cells strongly differed in cisplatin sensitivity. As an overall consideration, tinzaparin co-treatment affected the response to cisplatin of A2780cis, but not A2780 tumors in the later experimental time range. A subgroup analysis confirmed that initially smaller A2780cis tumors benefit from tinzaparin, but also small A2780 xenografts. Tinzaparin did not affect cisplatin accumulation in A2780cis xenografts, but strongly increased the platinum content in A2780, obviously related to morphological differences in both xenografts. Although we cannot directly confirm a return of A2780cis cisplatin resistance by tinzaparin, as shown in vitro, the present findings give reason to discuss heparin effects on cytostatic drug efficiency for small tumors and warrants further investigation. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessArticle

New Insights in Thrombin Inhibition Structure–Activity Relationships by Characterization of Octadecasaccharides from Low Molecular Weight Heparin

by Pierre A. J. Mourier, Olivier Y. Guichard, Fréderic Herman, Philippe Sizun and Christian Viskov

Molecules 2017, 22(3), 428; https://doi.org/10.3390/molecules22030428 - 8 Mar 2017

Cited by 7 | Viewed by 5913

Abstract

Low Molecular Weight Heparins (LMWH) are complex anticoagulant drugs that mainly inhibit the blood coagulation cascade through indirect interaction with antithrombin. While inhibition of the factor Xa is well described, little is known about the polysaccharide structure inhibiting thrombin. In fact, a minimal [...] Read more.

Low Molecular Weight Heparins (LMWH) are complex anticoagulant drugs that mainly inhibit the blood coagulation cascade through indirect interaction with antithrombin. While inhibition of the factor Xa is well described, little is known about the polysaccharide structure inhibiting thrombin. In fact, a minimal chain length of 18 saccharides units, including an antithrombin (AT) binding pentasaccharide, is mandatory to form the active ternary complex for LMWH obtained by alkaline β-elimination (e.g., enoxaparin). However, the relationship between structure of octadecasaccharides and their thrombin inhibition has not been yet assessed on natural compounds due to technical hurdles to isolate sufficiently pure material. We report the preparation of five octadecasaccharides by using orthogonal separation methods including size exclusion, AT affinity, ion pairing and strong anion exchange chromatography. Each of these octadecasaccharides possesses two AT binding pentasaccharide sequences located at various positions. After structural elucidation using enzymatic sequencing and NMR, in vitro aFXa and aFIIa were determined. The biological activities reveal the critical role of each pentasaccharide sequence position within the octadecasaccharides and structural requirements to inhibit thrombin. Significant differences in potency, such as the twenty-fold magnitude difference observed between two regioisomers, further highlights the importance of depolymerisation process conditions on LMWH biological activity. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Review

Jump to: Editorial, Research

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Open AccessReview

From Farm to Pharma: An Overview of Industrial Heparin Manufacturing Methods

by Jan-Ytzen Van der Meer, Edwin Kellenbach and Leendert J. Van den Bos

Molecules 2017, 22(6), 1025; https://doi.org/10.3390/molecules22061025 - 21 Jun 2017

Cited by 85 | Viewed by 12768

Abstract

The purification of heparin from offal is an old industrial process for which commercial recipes date back to 1922. Although chemical, chemoenzymatic, and biotechnological alternatives for this production method have been published in the academic literature, animal-tissue is still the sole source for [...] Read more.

The purification of heparin from offal is an old industrial process for which commercial recipes date back to 1922. Although chemical, chemoenzymatic, and biotechnological alternatives for this production method have been published in the academic literature, animal-tissue is still the sole source for commercial heparin production in industry. Heparin purification methods are closely guarded industrial secrets which are not available to the general (scientific) public. However by reviewing the academic and patent literature, we aim to provide a comprehensive overview of the general methods used in industry for the extraction of heparin from animal tissue. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessReview

Sulfated Alginates as Heparin Analogues: A Review of Chemical and Functional Properties

by Øystein Arlov and Gudmund Skjåk-Bræk

Molecules 2017, 22(5), 778; https://doi.org/10.3390/molecules22050778 - 11 May 2017

Cited by 54 | Viewed by 8866

Abstract

Heparin is widely recognized for its potent anticoagulating effects, but has an additional wide range of biological properties due to its high negative charge and heterogeneous molecular structure. This heterogeneity has been one of the factors in motivating the exploration of functional analogues [...] Read more.

Heparin is widely recognized for its potent anticoagulating effects, but has an additional wide range of biological properties due to its high negative charge and heterogeneous molecular structure. This heterogeneity has been one of the factors in motivating the exploration of functional analogues with a more predictable modification pattern and monosaccharide sequence, that can aid in elucidating structure-function relationships and further be structurally customized to fine-tune physical and biological properties toward novel therapeutic applications and biomaterials. Alginates have been of great interest in biomedicine due to their inherent biocompatibility, gentle gelling conditions, and structural versatility from chemo-enzymatic engineering, but display limited interactions with cells and biomolecules that are characteristic of heparin and the other glycosaminoglycans (GAGs) of the extracellular environment. Here, we review the chemistry and physical and biological properties of sulfated alginates as structural and functional heparin analogues, and discuss how they may be utilized in applications where the use of heparin and other sulfated GAGs is challenging and limited. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessReview

New Applications of Heparin and Other Glycosaminoglycans

by Marcelo Lima, Timothy Rudd and Edwin Yates

Molecules 2017, 22(5), 749; https://doi.org/10.3390/molecules22050749 - 6 May 2017

Cited by 61 | Viewed by 7954

Abstract

Heparin, the widely used pharmaceutical anticoagulant, has been in clinical use for well over half a century. Its introduction reduced clotting risks substantially and subsequent developments, including the introduction of low-molecular-weight heparin, made possible many major surgical interventions that today make heparin an [...] Read more.

Heparin, the widely used pharmaceutical anticoagulant, has been in clinical use for well over half a century. Its introduction reduced clotting risks substantially and subsequent developments, including the introduction of low-molecular-weight heparin, made possible many major surgical interventions that today make heparin an indispensable drug. There has been a recent burgeoning of interest in heparin and related glycosaminoglycan (GAG) polysaccharides, such as chondroitin sulfates, heparan sulfate, and hyaluronate, as potential agents in various applications. This ability arises mainly from the ability of GAGs to interact with, and alter the activity of, a wide range of proteins. Here, we review new developments (since 2010) in the application of heparin and related GAGs across diverse fields ranging from thrombosis and neurodegenerative disorders to microbiology and biotechnology. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessReview

Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease

by Erik G. Hayman, Akil P. Patel, Robert F. James and J. Marc Simard

Molecules 2017, 22(5), 724; https://doi.org/10.3390/molecules22050724 - 2 May 2017

Cited by 25 | Viewed by 8126

Abstract

Pharmacologic efforts to improve outcomes following aneurysmal subarachnoid hemorrhage (aSAH) remain disappointing, likely owing to the complex nature of post-hemorrhage brain injury. Previous work suggests that heparin, due to the multimodal nature of its actions, reduces the incidence of clinical vasospasm and delayed [...] Read more.

Pharmacologic efforts to improve outcomes following aneurysmal subarachnoid hemorrhage (aSAH) remain disappointing, likely owing to the complex nature of post-hemorrhage brain injury. Previous work suggests that heparin, due to the multimodal nature of its actions, reduces the incidence of clinical vasospasm and delayed cerebral ischemia that accompany the disease. This narrative review examines how heparin may mitigate the non-vasospastic pathological aspects of aSAH, particularly those related to neuroinflammation. Following a brief review of early brain injury in aSAH and heparin’s general pharmacology, we discuss potential mechanistic roles of heparin therapy in treating post-aSAH inflammatory injury. These roles include reducing ischemia-reperfusion injury, preventing leukocyte extravasation, modulating phagocyte activation, countering oxidative stress, and correcting blood-brain barrier dysfunction. Following a discussion of evidence to support these mechanistic roles, we provide a brief discussion of potential complications of heparin usage in aSAH. Our review suggests that heparin’s use in aSAH is not only safe, but effectively addresses a number of pathologies initiated by aSAH. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessReview

Heparin, Heparan Sulphate and the TGF-β Cytokine Superfamily

by Chris C. Rider and Barbara Mulloy

Molecules 2017, 22(5), 713; https://doi.org/10.3390/molecules22050713 - 29 Apr 2017

Cited by 85 | Viewed by 9221

Abstract

Of the circa 40 cytokines of the TGF-β superfamily, around a third are currently known to bind to heparin and heparan sulphate. This includes TGF-β1, TGF-β2, certain bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), as well as GDNF and two [...] Read more.

Of the circa 40 cytokines of the TGF-β superfamily, around a third are currently known to bind to heparin and heparan sulphate. This includes TGF-β1, TGF-β2, certain bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), as well as GDNF and two of its close homologues. Experimental studies of their heparin/HS binding sites reveal a diversity of locations around the shared cystine-knot protein fold. The activities of the TGF-β cytokines in controlling proliferation, differentiation and survival in a range of cell types are in part regulated by a number of specific, secreted BMP antagonist proteins. These vary in structure but seven belong to the CAN or DAN family, which shares the TGF-β type cystine-knot domain. Other antagonists are more distant members of the TGF-β superfamily. It is emerging that the majority, but not all, of the antagonists are also heparin binding proteins. Any future exploitation of the TGF-β cytokines in the therapy of chronic diseases will need to fully consider their interactions with glycosaminoglycans and the implications of this in terms of their bioavailability and biological activity. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Open AccessReview

Functional Assays in the Diagnosis of Heparin-Induced Thrombocytopenia: A Review

by Valentine Minet, Jean-Michel Dogné and François Mullier

Molecules 2017, 22(4), 617; https://doi.org/10.3390/molecules22040617 - 11 Apr 2017

Cited by 69 | Viewed by 9744

Abstract

A rapid and accurate diagnosis in patients with suspected heparin-induced thrombocytopenia (HIT) is essential for patient management but remains challenging. Current HIT diagnosis ideally relies on a combination of clinical information, immunoassay and functional assay results. Platelet activation assays or functional assays detect [...] Read more.

A rapid and accurate diagnosis in patients with suspected heparin-induced thrombocytopenia (HIT) is essential for patient management but remains challenging. Current HIT diagnosis ideally relies on a combination of clinical information, immunoassay and functional assay results. Platelet activation assays or functional assays detect HIT antibodies that are more clinically significant. Several functional assays have been developed and evaluated in the literature. They differ in the activation endpoint studied; the technique or technology used; the platelet donor selection; the platelet suspension (washed platelets, platelet rich plasma or whole blood); the patient sample (serum or plasma); and the heparin used (type and concentrations). Inconsistencies in controls performed and associated results interpretation are common. Thresholds and performances are determined differently among papers. Functional assays suffer from interlaboratory variability. This lack of standardization limits the evaluation and the accessibility of functional assays in laboratories. In the present article, we review all the current activation endpoints, techniques and methodologies of functional assays developed for HIT diagnosis. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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Non-Anticoagulant Heparins Are Hepcidin Antagonists for the Treatment of Anemia

by Maura Poli, Michela Asperti, Paola Ruzzenenti, Annamaria Naggi and Paolo Arosio

Molecules 2017, 22(4), 598; https://doi.org/10.3390/molecules22040598 - 8 Apr 2017

Cited by 18 | Viewed by 6656

Abstract

The peptide hormone hepcidin is a key controller of systemic iron homeostasis, and its expression in the liver is mainly regulated by bone morphogenetic proteins (BMPs), which are heparin binding proteins. In fact, heparins are strong suppressors of hepcidin expression in hepatic cell [...] Read more.

The peptide hormone hepcidin is a key controller of systemic iron homeostasis, and its expression in the liver is mainly regulated by bone morphogenetic proteins (BMPs), which are heparin binding proteins. In fact, heparins are strong suppressors of hepcidin expression in hepatic cell lines that act by inhibiting the phosphorylation of SMAD1/5/8 proteins elicited by the BMPs. The inhibitory effect of heparins has been demonstrated in cells and in mice, where subcutaneous injections of non-anticoagulant heparins inhibited liver hepcidin expression and increased iron bioavailability. The chemical characteristics for high anti-hepcidin activity in vitro and in vivo include the 2O-and 6O-sulfation and a molecular weight above 7 kDa. The most potent heparins have been found to be the super-sulfated ones, active in hepcidin suppression with a molecular weight as low as 4 kDa. Moreover, the alteration of endogenous heparan sulfates has been found to cause a reduction in hepcidin expression in vitro and in vivo, indicating that heparins act by interfering with the interaction between BMPs and components of the complex involved in the activation of the BMP/SMAD1/5/8 pathway. This review summarizes recent findings on the anti-hepcidin activity of heparins and their possible use for the treatment of anemia caused by hepcidin excess, including the anemia of chronic diseases. Full article

(This article belongs to the Special Issue Looking Forward to the Future of Heparin: New Sources, Developments and Applications)

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